The insulin like growth factor (IGF) system plays a critical role in brain development and growth. However, in most/n vitro studies the activation of this system is overlooked. Standard culture media contains superphysiological levels of insulin thatactivate the IGF type 1 receptor (IGF-1R) in addition to the insulin receptor (IR). I have preliminary data demonstrating that IGF2 produces distinct effects from IGF1 on neural stem cells (NSC). My data reveal a vital role for IGF2 in NSC self-renewal, maintenance and growth. Therefore, the goal of this proposal is to determine the specific effects of IGF2 on NSC, to determine the receptors responsible for these effects and to evaluate the necessity of IGF2 for NSC growth/n vitro and in vivo. Completing these studies will demonstrate the importance of the IGF system in NSC maintenance and growth, with a specific focus on the role of IGF2 which is present at high levels within the brain. The first aim will determine which IGF2 signaling receptors are expressed on NSC. Aim 2 will establish how IGF2 maintains the NSC population and affects growth. Aims 3 and 4 will determine whether IGF2 is essential for NSC homeostasis and for exercise induced neurogenesis. The use of high dose insulin may stimulate the entire IGF system, but the many side effects eliminate this from being a potential therapeutic option in vivo. Therefore, these studies may recommend the use of IGF2 or an analog as potential therapeutics for expanding NSC in vivo. This application proposes to elucidate the role of IGF2 in neural stem cell self-renewal, maintenance and growth. Stem cells are a future therapy for many neurological diseases which are currently without any cure. The fundamental information obtained from my studies will enhance our ability to culture stem cells for therapeutic use.